Dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals, and itself possesses intrinsic pharmalogical properties. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth (Biochemical Pharmacology of Midbrain Dopamine Neurons. In: Psychopharmacology: The fourth generation of progress, F. E. Bloom and D. J. Kupfer, Eds., Raven Press, N.Y., 1995, pp 227-243). One group of compound studied extensively is that of pharmacologic agents that modify dopamine release or the release of other neurotransmitters.
Control of dopamine or neurotransmitter release is an important utility in-and-of itself. Studies of dopamine and neurotransmitter release have led to the discovery of important pharmacologically active compounds. However, new and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in as yet poorly controlled disease states or behavior models.
For example, dementia, such as is seen with Alzheimer's disease or Parkinsonism, remains largely untreatable. Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention-Deficit Disorder (ADD). Specific agents for treatment of these and related disorders are few in number or non-existent. behavioral disorder Attention-Deficit Disorder (ADD). Specific agents for treatment of these and related disorders are few in number or non-existent.
One means of studying neurotransmitter release is to study the activation of cholinergic channel mediated release (Wonanacott et al., Presynaptic nicotinic autoreceptors and heteroreceptors in the CNS. In: Effects of Nicotine on Biological Systems II: Advances in Pharmacological Sciences. P. B. S. Clark et al, Eds., Birkhauser, Basel, 1995, pp. 87-94). The biological effects of acetylcholine, for example, are mediated by distinct specific interactions with different subtypes of cholinergic receptors. The two distinct subfamilies of cholinergic receptors are defined as nicotinic cholinergic receptors and muscarinic cholinergic receptors. (See Taylor, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed.) The responses of these receptor families are mediated by two entirely different classes of second messenger systems. Nicotinic receptor activation mediates the conductance of specific extracellular ions (e.g. Na.sup.+, K.sup.+ and Ca.sup.++) through the neuronal membrane, whereas muscarinic receptors are coupled to intracellular systems that contain complex molecules such as G-proteins and inositol phosphates. Thus, the biological consequences of nicotinic cholinergic channel activation by acetylcholine are distinct from those of muscarinic activation. In an analogous manner, inhibition of nicotinic cholinergic channels result in still other effects distinct and different from those arising from muscarinic receptor inhibition.
In fact, there is reason to expect or suggest that agents that control neurotransmitter release and which bind at the nicotinic cholinergic receptors may show activity in addressing some untreatable disorders of the central nervous system, including those mentioned above. Partial evidence in support of this suggestion is set forth briefly below.
The precise molecular lesions that contribute to the morphological and functional deficits associated with dementia are not fully understood, despite intensive research efforts. However, the most consistent abnormality for Alzheimer's disease, as well as for vascular dementia and cognitive impairment due to organic brain disease related to alcoholism, is the degeneration of the cholinergic system arising from the basal forebrain (BF) to both the cortex and hippocampus (Bigl et al., in Brain Cholinergic Systems, M. Steriade and D. Biesold, eds., Oxford University Press, Oxford, 1990, pp. 364-386). In particular, neurochemical evidence from the brains of patients afflicted with Alzheimer's disease has revealed reliable decreases in markers of cholinergic neuronal function (Perry et al., Br. Med. J., 2:1457, 1978; Reisine et al., Brain Res., 159:477, 1978; Coyle et al., Science, 219:1184, 1983; and McGeer et al., Neurology, 34:741, 1984). While there are a number of other neurotransmitter systems affected by Alzheimer's disease (Davies, Med. Res. Rev., 3:221, 1983), the relative occurrence of such abnormalities is less consistent or the effect is less profound than the decreases in these cholinergic neuronal function markers. More specifically, substantial reductions (30-50%) in nicotinic cholinergic channel receptors have been consistently reported in the brains of patients with Alzheimer's disease or Parkinson's disease (Kellar et al., Brain Res., 436:62, 1987; and Whitehouse et al., Neurol., 38:720, 1988), whereas changes in muscarinic cholinergic receptors are less remarkable and more dependent or receptor subtype.
However, degeneration of the cholinergic neurotransmitter system has also been reported in aged, but otherwise healthy, individuals (for a review, see Giacobini, J. Neurosci. Res., 27:548, 1990). Moreover, aging may cause a decrease in the cholinergic impulses flow from the basal forebrain to the cortex (Aston-Jones et al., Brain Res., 325:271, 1985). Consistent with these findings are pharmacological studies suggesting that cholinergic mechanisms are, at least in part, responsible for the memory disturbances in aged animals and humans not suffering from Alzheimer's disease (Drachman and Leavitt, Arch. Neurol., 30:113, 1974; Bartus et al., Science, 217:408, 1982).
Other clinical signs associated with the neurodegenerative process of Alzheimer's disease include decreases in regional cerebral blood flow and cerebral glucose utilization, in regions which largely parallel the areas where cholinergic deficits occur (Ingvar and Risberg, Exp. Brain Res., 3:195, 1962; Ingvar et al., Aging: Alzheimer's Disease, Senile Dementia and Related Disorders, Vol. 7, R. Katzman, R. D. Terry, and K. L. Bick, eds., Raven Press, 1978, p. 203; and Dastur, J. Cerebral Blood Flow & Metabol., 5:1, 1985). Recent clinical evidence suggests that this abnormality observed in Alzheimer's disease patients reflects regional nicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging, 11:262, 1990). In agreement with this finding, is the discovery that regulation of cerebral blood flow in the frontopariet al cortex in the rat, governed by the basal forebrain, is also dependent upon nicotinic mechanisms (Arneric, J. Cerebral Blood Flow & Metabol., 2 (Suppl. 1): S502, 1989).
Pilot clinical studies suggest that nicotine may be useful for the acute treatment of deficits in attention and information processing associated with Alzheimer's disease (Sahakian et al., Brit. J. Psych., 154:797, 1989; Newhouse et al., Psychopharmacol., 95:171, 1988). It has been shown that both acutely- and chronically-administered nicotine enhances cognitive function in rats (Levin et al., Behav. Neural Biol., 53:269, 1990), an effect that is also observed in aged animals (Cregan et al., Soc. Neurosci. Abstract, 15: 2952, 1989). Nicotine is expected to be neuroprotective, because it has been shown that nicotine can prevent pre-synaptic loss of functional dopaminergic neurons in animal studies with induced brain injuries (Janson et al., Prog. Brain Res., 79:257, 1989; and Owman et al., Prog. Brain Res., 79:267, 1989).
Other situations where beneficial therapeutic outcome may be achieved or improved through administrrtion of nicotine or a cholinergic channel activator, because of neurotransmitter releasing and anxiolytic properties of these agents, include attention-deficit disorder and drug withdrawal.
Attention-deficit disorder (ADD), with or without hyperactivity, is a behavioral disorder characterized by distractibility and impulsiveness. Children with this disorder are handicapped by their inability to concentrate and control their impulsivity, especially in settings requiring sustained attention, for example, in school. Neurochemically, ADD is thought to be the result of a decreased release of dopamine (Oades, R. D., Prog. Neurobiol., 29:365-391, 1987; Rogeness et al., J. Am. Acad. Child Adolescent Psychiatry, 31:765-781, 1992; Shenker, A., Adv. Pediatr., 39:337-382, 1992). Dopaminergic stimulation has been shown to be important in further regulating the release of acetylcholine from areas of the brain involved with attentional precessing such as the cerebral cortex and hippocampus (Day, J. and Fibiger, H. C., Synapse, 12:281-286, 1992). Nicotine, d-amphetamine and methylphenidate each enhance the release of dopamine and acetylcholine (Day, J. and Fibiger, H. C., Neuroscience, 54:643-648, 1993), although by different pharmacological mechanisms (Lefkowitz, R. J., Hoffman, B. B., and Taylor, P., Neurohumoral transmission: The autonomic and somatic motor nervous systems. In: Goodman and Gilman's, The Pharmacological Basis of Therapeutics, (eds. A. G. Gilman, T. W. Rall, A. S. Nies, P. Taylor) Pergamon Press, New York, 1990, pp. 244-268.). While a cure for this disorder has not been found, stimulants, such as d-amphetamine and methylphenidate which enhance the release of dopamine and acetylcholine, have been used successfully in management of the behavioral manifestations of ADD. Nicotine, because of its ability to improve concentration and task performance (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986; and D. M. Warburton and K. Wesnes in Smoking Behavior, R. E. Thornton, ed., Churchill-Livingston, Edinburgh, 1978, pp. 19-43) is also potentially useful in treating ADD. Pilot clinical studies using transdermal patches containing nicotine recently have been shown to improve the symptoms of ADD (Levine et al., Soc. for Research on Nicotine and Tobacco, Mar. 24-25, P63, 1995). Thus, enhancing the release of dopamine and acetylcholine with other compounds that activate nicotinic cholinergic channels may also have clinical utility in treating the symptoms of ADD, especially, if those compounds have a safer side effect profile compared to nicotine.
Schizophrenia is considered to be the result of overactive dopamine release (Kahn, R. S. and David, K L., New Developments in dopamine and schizophrenia In: Psychopharmacology: The fourth generation of progress, op. cit). Thus compounds that inhibit dopamine might be useful in the treatment of this condition. Evidence for the potential benefits of nicotinic cholinergic channel receptor-based therapies in schizophrenia come from the observation that certain nicotinic channel ligands have been shown to be neuroprotective (e.g., Freedman et al., In: Effects of Nicotine on Biological Systems II, Advances in Pharmacological Sciences, op. cit., pp.307-312; Martin et al., Drug Dev. Res., 31:135-141, 1994; Akaike et al., Brain Res 644:181-187, 1994; Marin et al., Neuroreport, 5:1977-1980, 1994). Epidemiologic data indicating increased prevalence of smoking among patients with schizophrenia (&gt;80%), may be an attempt to self-medicate both for palliative and neuroprotective benefits. Moreover, given the cognition-enhancing potential of nicotinic channel modulators, and the ability of (-)-nicotine to normalize sensory-gating impairments, it is possible that such compounds may be useful in treating two major dysfunctional manifestations of schizophrenia.
Parkinsonism is a clinical syndrome with four cardinal features: bradykinesia, muscular rigidity, resting tremor, and abnormalities of posture and gait. Classical investigations have clearly established that the basal ganglia and the nigrostriatal dopamine system as the site of the fundamental neurochemical lesion of the disease (Korczyn, A. D., Parkinson's Disease. In: Psychopharmacology: The Fourth Generation of Progress, op. cit., pp. 1479-1484.). Clinical studies have demonstrated the efficacy of restoring dopamine release, or mimic dopamine receptor activation. The therapeutic effects of nicotine in Parkinson's disease were described more than half a century ago (Moll, Brit. Med. J. 1: 1079, 1926), and interest has been renewed more recently (Janson et al., In: Effects of Nicotine on Biological Systems II, Advances in Pharmacological Sciences, op. cit., pp. 321-328). In addition, nicotine has been employed as a potential drug in the treatment of another movement disorder, Tourette's disease (McConville et al., Am. J. Psychiatry, 148:739, 1991; Silver et al, In: Effects of Nicotine on Biological Systems II, Advances in Pharmacological Sciences, op. cit., pp. 293-299.). Development of compounds that provide a more selective and persistent depolarization of cholinergic channel receptors in the brain than nicotine may provide a safer and more effective treatment of Parkinson's disease and related movement disorders.
The nicotine withdrawal syndrome associated with smoking cessation is characterized by craving for nicotine, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate and increased appetite and weight gain. Nicotine has, not surprisingly, been found to ease the withdrawal experienced by those attempting to break tobacco dependencies. As early as 1942, Johnston reported (L. Johnston, Lancet, 2:742, 1942) that injections of nicotine relieved the withdrawal symptoms experienced by cigarette smokers when they stopped smoking. More recently, in double-blind studies, nicotine was far superior to a placebo in suppressing or preventing the appearance of many of the signs and symptoms of withdrawal (J. R. Hughes et al., Psychopharmacology, 83:82-7, 1984; N. G. Schneider et al., Addictive Behavior, 2:149-56, 1984; R. J. West et al., Journal of Addiction, 79:215-9, 1984; K. O. Fagerstrom in Nicotine Replacement: a Critical Evaluation, O. F. Pomperleau and C. S. Pomperleau, eds., Alan R. Liss, Inc., New York, 1988, pp. 109-28; and J. E. Henningfield and D. R. Jasinski, ibid, pp.35-61). Irritability and impatience were shown to have been reduced in at least five independent controlled studies, while anxiety and difficulty concentrating were shown to have been reduced in at least two studies. One approach to alleviating the symptoms of tobacco withdrawal has been to develop more efficient methods of delivering nicotine, itself, for example, in transdermal patches (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986). The major problem with this approach is the non-selective effect of nicotine and in particular, the stimulant effects of increasing cardiac workload and oxygen demand that nicotine has on the heart. A selective cholinergic channel activator would be expected to be equally efficacious in relieving withdrawal symptoms with fewer cardiovascular liabilities.
Existing cholinergic channel agonists are therapeutically sub-optimal in treating the conditions discussed above. For example, such compounds have unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., (-)-nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine). In addition, other agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al., in: Nicotine Psychopharmacology, S. Wonnacott, M. A. H. Russell, & I. P. Stolermnan, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Theropy, E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336).
Various heterocyclic 2-pyrrolidinyloxy-substituted compounds with analgesic and hypotensive activities have been disclosed by Scheffler et al. (U.S. Pat. No. 4,643,995) and Tomioka et al. (Chem. Pharm. Bull, 38:2133-5, 1990).
Certain other 2-pyridyloxy-substituted compounds are disclosed inter alia by Engel et al. in U.S. Pat. No. 4,946,836 as having analgesic activity.
Various other compounds having a pyrrolidine or azetidine moiety substituted at the 3-position with a heterocycloxy group have also been disclosed (cf. U.S. Pat. Nos. 4,592,866 to A. D. Cale; 4,705,853 to A. D. Cale; 4,956,359 to Taylor et al.; and 5,037,841 to Schoehe et al. and European patent application EP296560A2, to Sugimoto et al.).